Animal feed and process

ABSTRACT

AN ANIMAL FEED FOR INCREASING MEAT, MILK OR EGG PRODUCTION COMPRISING A COMPOUND OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA:   1-(F3C-),4-R1,6-(R2,R3-PHENYL),R4,R5-4H-S-TRIAZOLO(4,3-A)   (1,4)BENZODIAZEPINE   WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL, OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND WHEREIN R2, R3, R4, AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL AS DEFINED ABOVE, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFINYL, ALKYLSULFONYL, DIALKYLAMINO, AND ALKANOYLAMINO, IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS IN COMBINATION WITH THE NUTRIENT FEED.

US. or. 424-269 United States Patent O 3,836,661 ANIMAL FEED AND PROCESSRobert J. Collins, 7127 Winter Forest Drive, Portage, Mich. 49081 NoDrawing. Filed Aug. 9, 1971, Ser. No. 170,318 The portion of the term ofthe patent subsequent to Sept. 17, 1991, has been disclaimed Int. Cl.A61k 27/00 6 Claims -ABSTRACT OF THE DISCLOSURE An animal feed forincreasing meat, milk or egg production comprising a compound of thegroup consisting of a compound of the formula:

Formula 1 wherein R is selected from the group consisting of hydrogenand alkyl, of 1 to 3 carbon atoms, inclusive, and wherein R R R and Rare selected from the group consisting of hydrogen, alkyl as definedabove, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, dialkylamino, and alkanoylamino, in whichthe carbon chain moieties are of 1 to 3 carbon atoms, inclusive, and thepharamcologically acceptable acid addition salts in combination with thenutrient feed.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related tocopending United States application Ser. No. 138,289, filed Apr. 28,1971, now abandoned, which discloses compounds of the Formula 1 andmethods for their preparation.

BRIEF SUMMARY OF THE INVENTION Broadly the present invention encompassesa nutrition ally adequate animal feed having dispersed therein acompound of the Formula 1 in sufficient concentration to pro videincreasing productivity and feed efliciencies in healthy meat-producing,milk-producing or egg-laying animals. The invention also includes theprocess of feeding the composition to meat-producing, milk-producing oregglaying animals.

DETAILED DESCRIPTION It has been found in recent years thatmeat-producing animals will gain more weight and gain it faster whenvarious classes of compounds such as vitamins, minerals, estrogens,antibiotics, and tranquilizers are added to the diet. Although thepresently available compounds are useful, new materials are still beingsought that would produce weight gains more rapidly, to a greaterextent, more efficiently with respect to feed intake at a lower cost andwithout undesirable side effects.

It is now possible by use of the present invention to obtain unexpectedresults in the feeding of meat-producing, milk-producing, or egg-layinganimals; that is to say, an increased rate of weight gain, an increasedamount of weight gain, an increase in milk production, or increased rateof egg laying, as well as increased feed efiiciency, can be obtained bythe addition of minute quantities of a compound of the Formula 1 to theanimals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed inUnited States application Ser. No. 138,- 289, filed Apr. 28, 1971.

Unless otherwise specified, all percentages are given on aweight-to-weight basis. The pound (1b.) weights given are avoirdupoisunits.

Feeding of the compositions of the present invention can commence forbirds shortly after hatching and in the case of mammals, during thecreep-feeding period of suckling animals when they are starting on solidfood and, of course, after weaning. Feeding of the compositions iscontinued throughout the growing period, lactation period, or egg-layingperiod.

The total concentration of the compound of the Formula l in the feedcomposition is determined with regard to the species of animal, age,weight, and average amount of feed consumed daily. Preferably thecompound of the Formula 1 is employed in the finished feed that willsupply the animal with a daily intake of from about 0.3 mg. to about 500mg. per head per day.

The following table illustrates the range of compound of Formula 1 inmilligrams daily dose per head per day for representative animals.

The foregoing dosage can generally be accomplished by providing fromabout 250 mg. to about 25,000 mg. of a compound of the Formula 1 per tonof finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of aliquid or solid premix wherein the concentration is -2000 times greaterthan the desired final concentration of the feed. For example, thecompound of Formula 1 can be dissolved or suspended in a fluid vehiclesuch as corn oil, cottonseed oil, molasses, distillers, solubles and thelike to prepare a fluid premix. Alternatively, a solid premix can beprepared by mixing a compound of the Formula 1 with an edible soliddiluent such as sucrose, lactose, starch, corn meal, flour, calciumcarbonate, soybean meal and the like.

Example 1 A diet for fattening lambs is prepared from the followingtypes and amounts of ingredients:

Percent Ground ear corn 82.05 Alfalfa meal 10.0 Soybean oil meal 44% 7.0Ground limestone 0.3 Salt 0.6 Trace mineral mixture 1 0.05

1 Contains the following percent of. minerals: Mn, 12; Co, 0.08; Fe,5.0; Cu, 0.4;1, 0.2-1;Zn. 0.7..

The above feed to be mixed, pelleted and offered to fattening lambsfree-choice in conjunction with hay.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 1.4 gm. of 8- chloro 6 phenyl 1(trifluoromethyl)-4H-s-triazolo- [4,3-a][1,4]benzodiazepine withsufficient corn meal to make one pound.

The feeding composition so prepared supplies 1.4 mg. of 8 chloro6-phenyl-1-(trifluoromethyl)-4H-s-triazolo- [4,3-a][1,4]benzodiazepineper pound of 3.1 parts per million.

The foregoing composition is usefully fed to lambs for increased rate ofweight gain and improved utilization of feed.

Example 2 A chicken feed for broilers is prepared from the followingtypes and amounts of ingredients:

Percent Yellow corn meal 67.35 Soybean oil meal 24.00 Menhaden fish meal6.00 Steamed bone meal 1.00 Ground limestone 1.00 Iodized salt .34 25%Choline chloride .13 Vitamin B supplement (6 mg./lb.) .10 Manganesesulfate .02 Supplemental vitamin mix 1 .06

(lonsisting of 16.0 gm. Vitamin A supplement (10 units/ mg); 3.6 gm.Vitamin D3 supplement (15,000 units/gm); 7.1 gm. riboflavin supplement(1 gm. riboflavin per ounce); 500 mg. niacin.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 2.0 gm. 8-ch1oro- 6-phenyl-1(trifluoromethyl)4H s triazolo[4,3 a]- [1,4]-benzodiazepine withsufiicient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 2.0 mg. 8 chloro 6phenyl-l-(trifluoromethyl)-4H-s-triazolo- [4,3-a] [1,4] benzodiazepineper pound, or about 4.4 parts per million.

The foregoing composition is usefully fed to chicken for increased rateof weight gain and improved utilization of feed. Similarly thecomposition can be fed to turkeys, duck and geese.

Example 3 A fattening feed for 800 pound yearling cattle is pre paredfrom the following types and amounts of ingredients:

Percent Ground ear corn 89.75 Soybean oil meal, 44% 9.0 Ground limestone0.7

Salt 0.5 Trace mineral mixture 1 0.05

Contains the following percent of minerals: Mn, 12; Co, 0.08 Fe, 5.0;Cu. 0.4 I, 0.24; Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 3.0 gm. of 8- chloro-6-phenyl 1(trifluoromethyl) 4H s triazol- [4,3-a] [1,4]benzodiazepine withsufiicient wheat flour to make 1 pound.

The feeding composition so prepared supplies 3.0 mg. of8-chlor0-6-phenyl 1 trifiuoromethyl) 4H s triaZolo[4,3-a][1,4]benzodiazepine per pound, or about 6.6 parts per million.

Cattle are to receive the foregoing feed ad libitum together with lb. ofhay per head per day and when so fed have an increased rate of weightgain and improved utilization of fe d.

4 Example 4 A swine diet for growing hogs of 40 to pounds body weight isprepared from the following types and amounts of ingredients:

Percent Corn, ground 78.15 Soybean oil meal, 44% 17.0 Meat and bonescraps, 50% 3.0 Oyster shell flour 0.4 Bone meal 0.5

Salt 0.5 Trace mineral mixture 1 0.05 Zin oxide 0.01 Vitamin A and Dsupplement 2 0.25 B Vitamin supplement 3 0.05 Vitamin B supplement 40.09

1 Contains the following percent of minerals: Mn, 12; Co, 0.08 Fe, 5.0;Cu, 0.4; I, 0.24 Zn, 0.7.

Contains 300 USP units Da/gm. and 1500 I.U.A./gm.

Contains per 1b. riboflavin, 200 mg.; calcium panto thenate, 4000 mg;niacin, 9000 mg.; and choline chloride 10,000 mg.

4 Contains 6 mg. Vitamin B12 per 1b.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 1.5 gm. of 8-chloro-6-phenyl 1trifluoromethyl) 4H s triazol- [4,3-a][1,4]benzodiazepine withsufiicient ground limestone to make one pound.

The feeding composition so prepared supplies 1.5 mg. of8-chloro-6-phenyl 1 (trifluoromethyl) 4H s triazolo[4,3-a][1,4]benzodiazepine per pound, or about 3.3 parts per million.

The foregoing composition is usefully fed to hogs for increased rate ofweight gain and improved utilization of feed.

Example 5 Following the procedure of the preceding examples 1 to 4,inclusive, animal feeds are similarly prepared substituting equimolaramounts of:

' 1-trifluoromethyl-9-isopropylsulfinyl-7-dimethylamino- 6-(o-bromophenyl) -4Hs-triazolo [4,3-a] [1,4] benzodiazepine;l-trifluoromethyl-10-chloro-4-methyl-6-(m-isopropylphenyl) 4H-s-triazolo[4,3-a] [1,4-1 benzodiazepine; 1-triflu0romethyl-9- dipropylamino -6-[p- (propionylamino)-phenyl) ]-4H-s-triazolo [4,3-a] [1,4]benzodiazepme; 1-trifluoromethyl- 8- methylsulfinyl) -6- o-nitrophenyl)4H-s-triazolo [4, 3-a] [1,4] benzodiazepine; 1-trifluoromethyl-7-(ethylsulfonyl -9-propyl-6- o-cyanophenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepine; 1-trifiuoromethyl-4-propyl-10-isopropyl-6-[mmethylthio)phenyl]-4H-s-triazo1o [4,3-a] [1,4] benzodiazepine;l-trifluoromethyl- 1 O-fluoro- 8-chloro-7-ethyl-6- [p- (trifluoromethylphenyl] -4H-s-triazolo [4,3-a] [1,4] benzodiazepine; 1-trifiuoromethyl-79-diethoxy- 10-methyl-6- m-ethoxyphenyl) -4H-s-triazolo [4,3-a] 1,4]benzodiazepine; 1-trifluoromethyl-7- propylthio 6- (m-bromophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine; 1-trifiuoromethyl-8-(acetylamino =6- (p-fiuorophenyl) 4H-s-triazolo[4,3-a] 1,4]benzodiazepine;

1-trifluoromethyl-4-propyl-6- (o-fiuorophenyl) -4H-striazolo[4,3-a][1,4] benzodiazepine;

1-trifluoromethyl-4-ethyl-9-methyl-6- [oethylthio -phenyl]-4H-s-triaZolo[4,3-a] [1,4] benzodiazepine;

1-trifiuoromethyl-4-methyl-7, l O-dichloro-S-ethyl-G-(misopropoxyphenyl)-4H-s-triazolo [4,3-a] 1,4]

benzodiazepine; 1-trilluoromethyl-9- (propionylamino) --propyl-6- [m-(propylthio) phenyl] -4H-s-triazolo [4,3-a] [1,4]

benzodiazepine; 1-trifi110romethyl-7- diisopropylamino -6-[p-dipropylamino) phenyl] -4H-s-triazolo [4,3-a] [1,4]

benzodiazepine;1-trifluor0methyl-4-isopropyl-7,9-dibromo-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine; l-trifiuoromethyl-8-chloro-9-ethyl-6- 3,4-dimethylphenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine;1-trifiuoromethyl-6- 2-methyl-4-methoxyphenyl) -4Hstriazolo [4,3-a] [1,4benzodiazepine; 1-trifiuoromethyl8-methylthio-9-methylsulfinyl-6-phenyl-4H-s-triazolo[4,3-a] 1,4] benzodiazepine;l-trifluoromethyl-8-methoxy-7-methylsulfonyl-6-phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine for the 8- [4,3-a][l,4]benzodiazepine of the examples.

I claim:

1. A process for increasing meat, milk, or egg production in a helahtymeat-producing, milk-producing or egglaying animal comprising thefeeding thereto of from about 0.03 to about 500 mg./ day of a compoundselected from the group consisting of a compound of the formula:

wherein R is selected from the group consisting of hydrogen and alkyl,of 1 to 3 carbon atoms, inclusive, and wherein R R R and R are selectedfrom the group consisting of hydrogen, alkyl as defined above, halogen,nitro, cyano, trifiuoromethyl, alkoxy, alkylthio, alkylsulfiinyl,alkylsulfonyl, dialkylarnino, and alkanoylamino, in which the carbonchain moieties are of 1 to 3 carbon atoms, inclusive, and apharmacologically acceptable acid addition salt thereof in combinationwith the nutrient animal feed.

2. The process of claim 1 wherein the member selected is in aconcentration of from 250 mg. to 25,000 mg. per pound of nutrientcarrier in the form of a premix.

3. The process of claim 1 when the member selected is in theconcentration from 500 mg. to 50,000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8- chloro6-phenyl-l-(trifluoromethyl)-4H-s-triazolo[4,3-a] [1,4] benzodiazepine.

5. The process of claim 2 wherein the compound is 8- chloro 6-phenyl-1-(trifluoromethyl) -4H-s-triazolo[4,3'a] l ,4] benzodiazcpine.

6. The process of claim 3 wherein the compound is 8- chloro6-phenyl-1-(trifiuoromethyl)-4H-s-triazolo[4,3-a] [1,4] benzodiazepine.

References Cited UNITED STATES PATENTS 3,646,055 2/1972 Hester, Jr424269 X FOREIGN PATENTS 6,916,543 5/ 1970 Netherlands 424269 OTHERREFERENCES J. Med. and Pharmaceutical Chemistry, vol. 1, #2 (1959), pp.121-122.

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner

